Tumor necrosis factor-alpha regulates the expression of inducible costimulator receptor ligand on CD34+ progenitor cells during differentiation into antigen presenting cells

The inducible costimulator receptor (ICOS) is a third member of the CD28 receptor family that regulates T cell activation and function. ICOS binds to a newly identified ligand on antigen presenting cells different from the CD152 ligands CD80 and CD86. We used soluble ICOSIg and a newly developed murine anti-human ICOS ligand (ICOSL) monoclonal antibody to further characterize the ICOSL during ontogeny of antigen presenting cells. In a previous study, we found that ICOSL is expressed on monocytes, dendritic cells, and B cells. To define when ICOSL is first expressed on myeloid antigen presenting cells, we examined ICOSL expression on CD34 cells in bone marrow. We found that CD34bright cells regardless of their myeloid commitment were ICOSL , whereas ICOSL was first expressed when CD34 expression diminished and the myeloid marker CD33 appeared

The effect of social exclusion on state paranoia and explicit and implicit self-esteem in a non-clinical sample

Background and objectives: The relationship between self-esteem and paranoia may be influenced by social stress. This study aimed to replicate previous research on the impact ofsocial exclusion on paranoia and self-esteem in a non-clinical sample and to extend this work by examining the effect of exclusion on self-esteem at the 'implicit' level. Methods: Non-clinical participants (N = 85) were randomly allocated to the Inclusion or Exclusion condition of a virtual ball-toss game ('Cyberball'). They completed self-reportmeasures of state paranoia and self-esteem, and two implicit measures of self-esteem - theImplicit Association Task (IAT) and Implicit Relational Assessment Procedure (IRAP) -prior to and after exposure to Cyberball. Results: Social exclusion increased state paranoia. This effect was moderated by distress associated with trait paranoia. Exclusion was also associated with decreased self-reported self-esteem, as well as reduced implicit self-esteem on the IAT. Changes in self-reported self-esteem were associated with state paranoia at post-Cyberball. The IRAP indicated that reductions in implicit self-esteem may be due to increases in 'Me-Negative' and 'Others-Positive' biases (rather than reductions in 'Me-Positive' bias). Limitations: The current study involved a non-clinical sample and so findings cannot be generalized to clinical paranoia. Conclusions: These findings are consistent with previous evidence that paranoia is associated with negative self-evaluations, whereas positive self-evaluations can persist in paranoia. They also provide support for the suggestion that investigations of self-esteem in paranoia should extend beyond global self-esteem and might benefit from a distinction between positive and negative components. (C) 2017 Elsevier Ltd. All rights reserved

Paying the Guard: An Entry-Guard-Based Payment System for Tor

When choosing the three relays that compose a circuit, Tor selects the first hop among a restricted number of relays called entry guards, pre-selected by the user himself. The reduced number of entry guards, that until recently was fixed to three, helps in mitigating the effects of several traffic analysis attacks. However, recent literature indicates that the number should be further reduced, and the time during which the user keeps the relays as guards increased. Therefore, developers of Tor recently proposed selecting only one entry guard, which is to be used by the user for all circuits and for a prolonged period of time (nine months). While this design choice was made to increase the security of the protocol, it also opens an unprecedented opportunity for a market mechanism where relays get paid for traffic by the users. In this paper, we propose to use the entry guard as the point-of-sale: users subscribe to their entry guard of choice, and deposit an amount that will be used for paying for the circuits. From the entry guard, income is then distributed to the other relays included in circuits through an inter-relay accounting system. While the user may pay the entry guard using BitCoins, or any other anonymous payment system, the relays exchange I Owe You (IOU) certificates during communication, and settle their balances only at synchronized, later points in time. This novel deferred payment approach overcomes the weaknesses of the previously proposed Tor payment mechanisms: we separate the user’s payment from the inter-relay payments, and we effectively unlink both from the chosen path, thus preserving the secrecy of the circuit

On the nature of surface roughness with application to contact mechanics, sealing, rubber friction and adhesion

Surface roughness has a huge impact on many important phenomena. The most important property of rough surfaces is the surface roughness power spectrum C(q). We present surface roughness power spectra of many surfaces of practical importance, obtained from the surface height profile measured using optical methods and the Atomic Force Microscope. We show how the power spectrum determines the contact area between two solids. We also present applications to sealing, rubber friction and adhesion for rough surfaces, where the power spectrum enters as an important input.Comment: Topical review; 82 pages, 61 figures; Format: Latex (iopart). Some figures are in Postscript Level

Determinants of postnatal spleen tissue regeneration and organogenesis

Abstract The spleen is an organ that filters the blood and is responsible for generating blood-borne immune responses. It is also an organ with a remarkable capacity to regenerate. Techniques for splenic auto-transplantation have emerged to take advantage of this characteristic and rebuild spleen tissue in individuals undergoing splenectomy. While this procedure has been performed for decades, the underlying mechanisms controlling spleen regeneration have remained elusive. Insights into secondary lymphoid organogenesis and the roles of stromal organiser cells and lymphotoxin signalling in lymph node development have helped reveal similar requirements for spleen regeneration. These factors are now considered in the regulation of embryonic and postnatal spleen formation, and in the establishment of mature white pulp and marginal zone compartments which are essential for spleen-mediated immunity. A greater understanding of the cellular and molecular mechanisms which control spleen development will assist in the design of more precise and efficient tissue grafting methods for spleen regeneration on demand. Regeneration of organs which harbour functional white pulp tissue will also offer novel opportunities for effective immunotherapy against cancer as well as infectious diseases

The UK prevalence of hereditary haemorrhagic telangiectasia and its association with sex, socioeconomic status and region of residence: a population-based study

Background Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder of aberrant blood vessel development characterised by arteriovenous malformations. HHT is associated with significant morbidity due to complications including epistaxis, gastrointestinal bleeding and stroke. We explored the hypothesis that a diagnosis of HHT is associated with sex, socioeconomic status and geographical location.Methods We used The Health Improvement Network, a longitudinal, computerised general practice database covering 5% of the UK population to calculate prevalence estimates for HHT stratified by age, sex, socioeconomic status and geographical location.Results The 2010 UK point prevalence for HHT was 1.06/10 000 person years (95% CI 0.95 to 1.17) or 1 in 9400 individuals. The diagnosed prevalence of HHT was significantly higher in women compared with men (adjusted prevalence rate ratio (PRR) 1.53, 95% CI 1.24 to 1.88) and in those from the most affluent socioeconomic group compared with the least (adjusted PRR 1.74, 95% CI 1.14 to 2.64). The PRR varied between different regions of the UK, being highest in the South West and lowest in the West Midlands (adjusted PRR for former compared with latter 1.86, 95% CI 1.61 to 2.15).Conclusions HHT prevalence is more common in the UK population than previously demonstrated, though this updated figure is still likely to be an underestimate. HHT appears to be significantly under-diagnosed in men, which is likely to reflect their lower rates of consultation with primary care services. There is under-diagnosis in patients from lower socioeconomic groups and a marked variation in the prevalence of diagnosis between different geographical regions across the UK that requires further investigation

Targeted apoptosis in ovarian cancer cells through mitochondrial dysfunction in response to Sambucus nigra agglutinin

Ovarian carcinoma (OC) patients encounter the severe challenge of clinical management owing to lack of screening measures, chemoresistance and finally dearth of non-toxic therapeutics. Cancer cells deploy various defense strategies to sustain the tumor microenvironment, among which deregulated apoptosis remains a versatile promoter of cancer progression. Although recent research has focused on identifying agents capable of inducing apoptosis in cancer cells, yet molecules efficiently breaching their survival advantage are yet to be classified. Here we identify lectin, Sambucus nigra agglutinin (SNA) to exhibit selectivity towards identifying OC by virtue of its specific recognition of α-2, 6-linked sialic acids. Superficial binding of SNA to the OC cells confirm the hyper-sialylated status of the disease. Further, SNA activates the signaling pathways of AKT and ERK1/2, which eventually promotes de-phosphorylation of dynamin-related protein-1 (Drp-1). Upon its translocation to the mitochondrial fission loci Drp-1 mediates the central role of switch in the mitochondrial phenotype to attain fragmented morphology. We confirmed mitochondrial outer membrane permeabilization resulting in ROS generation and cytochrome-c release into the cytosol. SNA response resulted in an allied shift of the bioenergetics profile from Warburg phenotype to elevated mitochondrial oxidative phosphorylation, altogether highlighting the involvement of mitochondrial dysfunction in restraining cancer progression. Inability to replenish the SNA-induced energy crunch of the proliferating cancer cells on the event of perturbed respiratory outcome resulted in cell cycle arrest before G2/M phase. Our findings position SNA at a crucial juncture where it proves to be a promising candidate for impeding progression of OC. Altogether we unveil the novel aspect of identifying natural molecules harboring the inherent capability of targeting mitochondrial structural dynamics, to hold the future for developing non-toxic therapeutics for treating OC

Isoprenoids increase bovine endometrial stromal cell tolerance to the cholesterol-dependent cytolysin from Trueperella pyogenes†

Preventing postpartum uterine disease depends on the ability of endometrial cells to tolerate the presence of the bacteria that invade the uterus after parturition. Postpartum uterine disease and endometrial pathology in cattle is most associated with the pathogen Trueperella pyogenes. Trueperella pyogenes secretes a cholesterol-dependent cytolysin, pyolysin, which causes cytolysis by forming pores in the plasma membrane of endometrial stromal cells. The aim of the present study was to identify cell-intrinsic pathways that increase bovine endometrial stromal cell tolerance to pyolysin. Pyolysin caused dose-dependent cytolysis of bovine endometrial stromal cells and leakage of lactate dehydrogenase into supernatants. Cell tolerance to pyolysin was increased by inhibitors that target the mevalonate and cholesterol synthesis pathway, but not the mitogen-activated protein kinase, cell cycle, or metabolic pathways. Cellular cholesterol was reduced and cell tolerance to pyolysin was increased by supplying the mevalonate-derived isoprenoid farnesyl pyrophosphate, or by inhibiting farnesyl-diphosphate farnesyltransferase 1 or geranylgeranyl diphosphate synthase 1 to increase the abundance of farnesyl pyrophosphate. Supplying the mevalonate-derived isoprenoid geranylgeranyl pyrophosphate also increased cell tolerance to pyolysin, but independent of changes in cellular cholesterol. However, geranylgeranyl pyrophosphate inhibits nuclear receptor subfamily 1 group H receptors (NR1H, also known as Liver X receptors), and reducing the expression of the genes encoding NR1H3 or NR1H2 increased stromal cell tolerance to pyolysin. In conclusion, mevalonate-derived isoprenoids increased bovine endometrial stromal cell tolerance to pyolysin, which was associated with reducing cellular cholesterol and inhibiting NR1H receptors

Esperanto for histones : CENP-A, not CenH3, is the centromeric histone H3 variant

The first centromeric protein identified in any species was CENP-A, a divergent member of the histone H3 family that was recognised by autoantibodies from patients with scleroderma-spectrum disease. It has recently been suggested to rename this protein CenH3. Here, we argue that the original name should be maintained both because it is the basis of a long established nomenclature for centromere proteins and because it avoids confusion due to the presence of canonical histone H3 at centromeres